MECHANISMS OF ONCOGENESIS PROGRAM: ABSTRACT The objectives of the Mechanisms of Oncogenesis (MOO) program are to elucidate the deregulated genetic and epigenetic events that drive tumor initiation and progression and to identify cancer relevant therapeutic targets. MOO is led by Wu, an expert in cancer signaling and mouse tumor models, and Renne, an expert in tumor virology and non-coding RNAs. MOO is a multidisciplinary group of 38 members, representing 19 departments from 5 colleges. Since 2016, 20 faculty, including 14 early stage investigators (ESIs) were recruited since 2016. The scientific aims of MOO are to: 1) elucidate the role of genetic and epigenetic alterations in cancer; 2) define the role of regulatory RNAs in oncogenesis; and, 3) translate MOO discoveries into novel therapeutic approaches. In alignment with Aim 3, Guryanova discovered that DNMT3A mutant AML was highly sensitive to low dose cytarabine, which has led to the development of a treatment trial in collaboration with Al-Mansour (CTHR), fostered by the ADs for Basic Sciences and Clinical Research and the IIT Think Tank. MOO has a peer- reviewed funding base of >$9M/yr in direct costs (increased >10% since 2019), representing 59 peer-reviewed projects of which 24 are from NCI ($3.8M direct costs), including an NCI P01, NIH, and other peer-reviewed sources. Since 2019, 10 new grants have been awarded to newly recruited ESIs. MOO cultivates intra- and inter- programmatic interactions through working group focused meetings (Epigenetics, Tumor Virology, and Lung Cancer, a catchment area priority), seminars, and annual program retreats. These interactions led to 11 active multi-PI peer-reviewed grants and a multi-institutional NCI P01. The success of MOO collaborations is also demonstrated by 762 cancer-related publications since 2016, 20% with impact factors >10. Moreover, 19% of publications are inter-programmatic, 23% are intra-programmatic, and 74% are multi-institutional. MOO members were also granted 36 new patents. MOO mentors trained 162 graduate students and 71 postdocs, comprised of 45% women and 10% underrepresented minorities (URM). There were 14 trainees (9 women; 3 URM) supported by NIH training grants. Wu serves as the program liaison to community outreach and engagement (COE). She and Renne convey the impact of MOO research to community members and, in return, learn about their needs. Renne, working with COE, co-developed the UFHCC cancer curriculum for Citizen Scientists. MOO leadership and members are committed to increase diversity, equity, and inclusion through participation in recruitment of trainees and faculty, in coordination with and guidance from the AD for Diversity, Equity, and Inclusion. Future goals, in alignment with the strategic plan, Momentum 2027, will be focused on paradigm shifting basic discovery and identification of therapeutic targets with the goal of clinical translation with CTHR and CCPS members to address the cancer burden in the CA. ...